AU730310B2

AU730310B2 - Dihydrobenzofuran compounds useful as anti-inflammatory agents

Info

Publication number: AU730310B2
Application number: AU18434/97A
Authority: AU
Inventors: Michael Wiard Scherz; Laurence Ichih Wu
Original assignee: Vanderbilt University
Current assignee: Vanderbilt University
Priority date: 1996-02-01
Filing date: 1997-01-30
Publication date: 2001-03-01
Anticipated expiration: 2017-01-30
Also published as: ES2221034T3; DE69729083D1; JP3095425B2; ATE266652T1; EP0891346A1; CA2244196C; US5672620A; CA2244196A1; CN1210528A; NO983531D0; AU1843497A; KR100322403B1; DK0891346T3; MX9806252A; JPH11504347A; DE69729083T2; EP0891346B1; NO983531L; CN1120838C; WO1997028148A1

Abstract

A compound having the structure: <IMAGE> wherein (a) n is from 1 to about 3; (b) X is selected from the group consisting of O, S, SO, or SO2; (c) Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to about 7 atoms; (d) Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; (e) W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and (f) R1 and R2 are independently hydrogen or straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R1 and R2 are bonded together to form a ring having from from 3 to about 7 atoms wherein one to three atoms may be heteroatoms. pharmaceutical compositions comprising such compounds, and methods of treating inflammation or pain using such compounds.

Description

WO 97/28148 PCT/US97/01316 1 DIHYDROBENZOFURAN COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS TECHNICAL FIELD The subject invention relates to nonsteroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds.

BACKGROUND OF THE INVENTION Certain dihydrobenzofuran compounds and other compounds structurally related thereto have been found to have significant disease altering activities.

Such compounds, processes for making them, and uses for them are disclosed in the following references: U.S. Patent No. 4,670,457 issued to Doria, Romeo Corno on June 2, 1987; U.S. Patent No. 4,849,428 issued to Dobson, Loomans, Matthews Miller on July 18, 1989; Japanese Patent Publication No. 53-005178 of Yoshitomi Pharm. Ind. KK published January 1, 1978; Hammond, M. I. E.

Kopka, R. A. Zambias, C. G. Caldwell, J. Boger, F. Baker, T. Bach, S. Luell D. E.

Maclntyre, "2,3-Dihydro-5-benzofuranols as Antioxidant-Based Inhibitors of Leukotriene Biosynthesis", J. Med. Chem., Vol. 32 (1989), pp. 1006-1020; Ortiz de Montellano, P. R M. A. Correia, "Suicidal Destruction of Cytochrome P-450 during Oxidative Drug Metabolism", Ann. Rev. Pharmacol. Toxicol., Vol. 23 (1983), pp. 481-503; Chakrabarti, R.J. Eggleton, P.T. Gallagher, J. Harvey, T.A.

Hicks, E.A. Kitchen, and C.W. Smith, "5-Acyl-3-substituted-benzofuran-2(3H)-ones as Potential Anti-inflammatory Agents", J. Med. Chem., Vol. 30 (1987), pp. 1663- 1668.

It is an object of the subject invention to provide compounds which have effective anti-inflammatory, analgesic and/or anti-oxidant activity.

It is a further object of the subject invention to provide such compounds which cause few adverse side effects.

It is also an object of the subject invention to provide methods for treating inflammation and/or pain using the subject compounds.

SUMMARY OF THE INVENTION The subject invention compounds having the structure: WO 97/28148 PCT/US97/01316 2 Y NW

Y

(CH

2 )n x R2 z Z wherein n is from 1 to about 3; X is selected from the group consisting of O, S, SO, or SO2; Y is independently hydrogen or straight, branched or cyclic alkyl or having from 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to about 7 atoms; Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and R1 and R2 are independently hydrogen or straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R 1 and R 2 are bonded together to form a ring having from 3 to about 7 atoms wherein one to three atoms may be heteroatoms.

DETAILED DESCRIPTION OF THE INVENTION As used herein, unless otherwise indicated, "alkyl" or "alkanyl" means a straight, branched or cyclic hydrocarbon chain, saturated or unsaturated, unsubstituted or substituted. Preferred alkyl are C 1

-C

1 0 more preferred are C 1 Cg; especially C 1

-C

4 Preferred alkyl are straight chain. Preferred branched alkyl have one or two branches, preferably one branch. Preferred cyclic alkyl are monocyclic or are a straight chain with a monocyclic terminus. Preferred alkyl are saturated. Unsaturated alkyl have one or more double bonds or/and one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Preferred alkyl are unsubstituted.

Preferred substituted alkyl are mono-, di-, or trisubstituted, more preferably monosubstituted. Preferred alkyl substituents include halo, hydroxy, oxo, alkoxy methoxy, ethoxy, propoxy, butoxy, pentoxy), aryloxy phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxyphenoxy, alkyloxycarbonylphenoxy, acyloxyphenoxy), acyloxy propionyloxy, benzoyloxy, acetoxy), carbamoyloxy, carboxy, mercapto, alkylthio, acylthio, arylthio phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, WO 97/28148 PCTfUS97/01316 3 alkyloxycarbonylphenylthio), aryl phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, heteroaryl, amino amino, mono- and di- C 1

-C

3 alkanylamino, methylphenylamino, methylbenzylamino),

C

1

C

3 alkanylamido, ureido, N'-alkylureido, N'N'-dialkylureidao, N'N'N-trialkylureido, guanidino, N'-alylguanidino, N',N",-dialkylguanidiniono or alkoxy carbonyl.

As used herein, "alkoxy" means -O-alkyl.

As used herein, "aryl" means a moiety having an unsubstituted or substituted aromatic ring having 6 to about 10 carbon atoms. Preferred aryl are phenyl and naphthyl; most preferred aryl is phenyl. Preferred aryl are unsubstituted. Preferred substituted aryl are mono-, di-, or trisubstituted, more preferably monosubstituted. Preferred aryl substituents include hydroxy, mercapto, halo, methyl, ethyl and propyl.

As used herein, "heterocyclyl" means a moiety having a saturated or unsaturated non-aromatic ring having from 3 to about 8 ring atoms, including from 2 to about 6 carbon atoms and from 1 to about 4 heteroatoms selected from O, S, and N. Preferred heterocycles are saturated. Preferred heterocycles have 5 or 6 atoms in the ring including 1 or 2 heteroatoms in the ring, also preferably 1 heteroatom in the ring. Specific preferred heterocycles include piperidinyl, tetrahydrothienyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, azepinyl, oxepinyl, thiepinyl, triazolidinyl, tetrazolidinyl. Heterocycles are unsubstituted or substituted, preferably unsubstituted. Preferred substituted heterocycles are mono-, di-, or trisubstituted, more preferably monosubstituted. Preferred heterocycle substituents include alkyl, halo, hydroxy, alkoxy, acyloxy, carboxy, carbamyloxy, thio, amino, amido, ureido, guanidino, thiocarbamamido, thioureido.

As used herein, "heteroaryl" means a moiety having an aromatic ring of 5 or 6 atoms including from 1 to 5 carbon atoms and from 1 to 4 heteroatoms selected from O, S, and N. Preferred heteroaryl groups include 1 to 3 heteroatoms in the ring, also preferably 1 or 2 heteroatom in the ring. Specific preferred heteroaryls include furyl, thienyl, pyrrolyl either unsubstituted or alkyl substituted on nitrogen, thiazolyl, oxazolyl, 5-imidazolyl either unsubstituted or alkyl-substituted on nitrogen, isoxazolyl, isothiazolyl, pyrazolyl unsubstituted or alkyl-substituted on nitrogen, oxdiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl. Fused heteroaryls include imidazothiazolinyl, imidazopyridinyl, imidazoimidazolinyl, indolyl, quinolyl, isoquinolyl. Heteroaryl groups are unsubstituted or substituted, preferably unsubstituted. Preferred substituted heteroaryls are mono-, di-, or WO 97/28148 PCTfUJS97/01316 4 trisubstituted, more preferably monosubstituted. Preferred heteroaryl substituents include alkyl, halo, hydroxy, alkoxy, thio, nitro, amino, nitro, amido, ureido, guanidino, thiocarbamamido, thioureido.

As used herein, "halo" means fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chloro and bromo, especially chloro.

Compounds The subject invention involves compounds having the following structure: Y NW

Y

R 1

(CH

2 )n I z wherein n is from 1 to about 3; X is selected from the group consisting of O, S, SO, or SO 2 Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to about 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from about 3 to about 7 atoms; Z is hydrogen or straight, branched or cyclic alkyl having from 3 to about 10 atoms other than hydrogen; W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and Ri and R2 are independently hydrogen or straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R 1 and R 2 are bonded together to form a ring having from from 3 to about 7 atoms wherein one to three atoms may be heteroatoms.

In the above structure, each Y is independently selected from hydrogen, straight or branched alkanyl having from 1 to about 4 carbon atoms, and cyclic alkyl having about 3 carbon atoms, cyclopropyl, or the Y's are bonded together to form an unsubstituted cyclic alkanyl ring having from 3 to about 7 carbon atoms in the ring. Each Y is preferably hydrogen, methyl, ethyl or cyclopropyl; more preferably hydrogen or methyl; most preferably methyl. Preferably both Y's are the same. When the Y's are bonded together to form a cyclic ring, the ring is preferably cyclopropyl, cyclobutyl or cyclopentyl, more preferably cyclopropyl.

WO 97/28148 PCT/US97/01316 In the above structure, Z is selected from branched or cyclic alkyl, and unsubstituted or alkanyl-substituted phenyl, or benzyl, Z having from 3 to about atoms other than hydrogen. Z is preferably saturated. Z is preferably branched alkanyl having from about 3 to about 8 carbon atoms, more preferably from about 4 to about 6 carbon atoms. Z is preferably branched alkanyl having 2 or more branches, more preferably 2 branches. Preferred branched alkanyl Z include tbutyl, neopentyl, isopropyl; most preferred is t-butyl. Preferred cyclic alkanyl Z include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. In the above structure, R1 and R2 are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms. R1 and R2 may be bonded together to form a cyclic alkanyl ring having from about 3 to about 7 atoms in the ring wherein 1 to about 3 atoms may be heteroatoms. Preferred heteroatoms are O, N, or S. Other preferred R groups include aryl, heterocyclyl, heteroaryl, hydroxy, or alkoxy.

Preferred compounds of the subject invention are included in the following table:

NW

NRi R2 Compound No. W R1 R2 1 OH H H 2 H H butyl 3 H methyl methyl 4 H -(CH2)4- In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. The anti-inflammatory activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to antagonize the local edema which is characteristic of the inflammatory response. Examples of such known tests include the rat carrageenan edema test, the oxazolone-induced inflamed mouse ear test, and the mouse arachadonic acid-induced inflamed ear test. Analgesic activity may be tested in art-known models such as the phenylbenzoquinone-induced writhing test in mice, WO 97/28148 PCT/US97/01316 6 and the Randall Selitto test in rats. Another useful art-known test is the rat adjuvant arthritis test which is a useful model for assessing anti-inflammatory activity, anti-arthritic and anti-resorptive activity in a chronic, rather than an acute, model.

These and other appropriate tests for pharmacological activity are disclosed and/or referred to in U.S. Patent No. 4,130,666 issued to Moore on December 19, 1978; U.S. Patent No. 4,431,656 issued February 14, 1984 to Katsumi, et al.; U.S.

Patent No. 4,440,784 issued to Katsumi, et al. on April 3, 1984; Japanese Patent Application 85/54315 of Katsumi, et al., published March 28, 1985; European Patent Application No. 0,059,090 of Yamanuchi Pharmaceutical Company Ltd., published September 1, 1982; Opas, R.J. Bonney J. L. Humes, "Prostaglandin and Leukotriene Synthesis in Mouse Ears Inflamed by Arachadonic Acid", The Journal of Investigative Dermatology, Vol. 84, No. 4 (1985), pp. 253- 256; Swingle, K. R. L. Bell G. G. I. Moore, "Anti-inflammatory Activity of Antioxidants", Anti-inflammatory and Antirheumatic Drugs, Vol. III, Chapter 4, K. D.

Rainsford, ed., CRC Press, Inc., (1985), pp. 105-126; Adamkiewicz, V. W. B.

Rice J. D. McColl, "Antiphlogistic Effect of Trypsin in Normal and in Adrenalectomized Rats", Canadian Journal of Biochemistry Physiology, Vol. 33 (1955), pp. 332-339; Sellye, "Further Studies Concerning the Participation of the Adrenal Cortex in the Pathogenesis of Arthritis", British Medical Journal, Vol. 2 (1949), pp. 1129-1135; and Winter, E. A. Risley G. W. Nuss, "Carrageenan-lnduced Edema in Hind Paw of the Rats as an Assay for Antiinflammatory Drugs" Proceedings of Society of Experimental Biology and Medicine, Vol. 111 (1962), pp. 544-547; Otterness, M. L. Bliven, "Laboratory Methods for Testing Nonsteroidal Antiinflammatory Drugs", Nonsteroidal Antiinflammatory Drugs, Chapter 3, J. G. Lombardino, ed., John Wiley Sons, Inc.

(1985), pp. 111-252. Hitchens, J. S. Goldstein, L. Shemano J. M. Beiler, "Analgesic Effects of Irritants in Three Models of Experimentally-Induced Pain", Arch. Int. Pharmacodyn., Vol. 169, No. 2 (1967) pp. 384-393; Milne, G. M. T. M.

Twomey, "The Analgetic Properties of Piroxicam in Animals and Correlation with Experimentally Determined Plasma Levels", Agents and Actions, Vol. 10, No. 1/2 (1980), pp. 31-37; Randall, L. 0. J. J. Selitto, "A Method for Measurement of Analgesic Activity on Inflamed Tissue", Arch. Int. Pharmacodyn., Vol. 111, No. 4 (1957), pp. 409-419; Winter, C. A. L. Faltaker, "Nociceptive Thresholds as Affected by Parenteral Administration of Irritants and of Various Antinociceptive Drugs", J. Pharmacol. Exp. Ther., Vol. 148, No. 3 (1965), pp. 373-379; the disclosure of all these references are incorporated herein by reference.

WO 97/28148 PCTIUS97/01316 7 Many anti-inflammatory drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs) cause undesirable gastrointestinal side effects, especially when dosed perorally; such side effects may include ulcers and erosions. These side effects, which are often asymptomatic, can become serious enough to require hospitalization and can even be lethal. Compounds of the subject invention generally cause fewer such gastrointestinal side effects compared to other NSAIDs. Some compounds of the subject invention are even gastroprotective, protecting the stomach and intestines from ulcers and erosions, particularly those caused by ethanol or other NSAIDs.

Certain NSAIDs, when dosed systematically, cause an undesirable increase in systemic levels of certain liver enzymes. Compounds of the subject invention generally cause little or no liver enzyme side effects.

Compounds useful in the subject invention can be made using the following general reaction schemes: The amidines can be prepared by two different routes. The first route involves conversion of the substituted benzene starting material to the corresponding nitrile with chlorosulfonylisocyanate and dimethylformamide. Reaction with acidic ethanol gives the imidate which is then reacted with the amine of choice to provide the amidine. The nitrile intermediate can be reacted with a hydroxylamine or an alkoxylamine to provide the N-hydroxyamidine or N-alkoxyamidine product. The second route involves conversion of the brominated benzene starting material to the aryl lithium by lithium halogen exchange with t-butyllithium followed by reaction with the appropriate N,N-disubstituted cyanamide.

WO 97/28148 PCTIUS97/01316 8 yY I. CISO 2 NCQ Y Y CN Y NH y NH 2. DMF (C HCI. EtOH R12N/R X (C 2)n X*C 3 z S NOR (CH 2)ny

NH

z yY Y Y NH Br 1. 1-auLi R, (CH2) (CH 2)n I 2X RI X R2 z R,2z Synthesis Examples The following non-limiting examples provide further information regarding synthesis of the subject compounds.

Example 1 N-Butvl-7-tert-butvl-2. 3-dihydro-3,3-dimethylbenzofuran-5-carboximidamide hydrochloride 7-tert-B utyl-5-cyano-2, 3-dihvd ro-3, 3-di methyl be nzofu ranA solution of 7-tert-butyl- 2,3-d ihyd robenzofu ran (16.75 g, 82 mmol) in CH2CI2 (175 mL) is heated to reflux, and chilorosulIfo nylisocyanate (3.5 eq, 287 mmol, 25.4 mL) is added in a single portion. The reaction is judged complete by TLC EtOAc hexanes) after 2 h.

The reaction mixture is then cooled to 0OC and IDMVF (10 eq, 0.82 mol, 65 mL) is added. The solution is allowed to stir at ambient temperature for 1.5 h. The solvents are evaporated and the resulting oil partitioned between hexanes (200 mL) and H20 (3 x 100 mnL). The aqueous phase is discarded, and the hexanes are dried (MgSO4) and evaporated to a yellow oil which solidifies upon sitting (18.2 g).

This solid is purified by medium pressure chromatography EtOAc hexanes) to give the desired compound (8.58 g, 46%) as a yellow oil of sufficient purity (approx 85% by 1 H-NMVR) for the next reaction.

Ethyl 7-tert-Butvl-2,3-dihydro-3,3-dimethylbenzofuran-5-carboximjidi acid hydrochloride WO 97/28148 PCTIUS97/01316 9 Into a solution of 7-tert-butyl-5-cyano-2,3-dihydro-3,3-dimethylbenzofuran (4.90 g, 18.6 mmol) in Et20 (30 mL) and EtOH (3 eq, 55.8 mmol, 3.2 mL) is bubbled HCI gas for 10 min. The resulting red solution is stirred at 23 *C for 4 days. The solvents are evaporated, the red oil triturated with hexanes (30 mL), and the resulting red solid collected by filtration to give the title compound as a red powder (3.55 g, 62%) of sufficient purity for the next reaction.

Step 3: N-Butyl-7-tert-butyl-2,3-dihydro-3.3-dimethylbenzofuran-5carboximidamide hydrochloride To a solution of ethyl 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran-5carboximidic acid hydrochloride (400 mg, 1.29 mmol) in dioxane (10 mL) is added excess butylamine (0.5 mL). A color change from red to yellow is observed during the addition, and a precipitate forms. The reaction is also monitored by TLC MeOH CHCI3). After 3 h, the white solid is collected by filtration and washed with MeOH to give the title compound as a white powder (243 mg, mp 236 237 oC.

Example 2 7-tert-Butyl-2.3-dihvdro-3,3-dimethyl-5-(imino-1-pvrrolidinylmethvl)-benzofuran hydrochloride To a solution of ethyl 7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran-5carboximidic acid hydrochloride (400 mg, 1.29 mmol) in dioxane (10 mL) is added excess pyrrolidine (0.6 mL). A color change from red to yellow is observed during the addition, and a precipitate forms The reaction is also monitored by TLC MeOH CHCI3). After 3 h, the yellow precipitate is collected by filtration and purified by preparative TLC (10% MeOH CHCI3) to give the desired product as a white powder (210mg, mp 255 256 oC.

WO 97/28148 PCTIUS97/01316 Example 3 7-tert-Butyl-2,3-dihvdro-N.N-dimethyl-3, 3 hydrochloride To a solution of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzofuran (500 mg, 1.8 mmol) in Et20 (0.6 mL), and hexanes (5.5 mL) at -78 0 C is added t-BuLi (1.5 M in hexanes, 2.9 eq, 5.3 mmol, 3.3 mL) at such a rate that the reaction temperature does not exceed -600C. This solution is stirred for 1 h and then slowly cannulated into a -78 0 C solution of dimethylcyanamide (1.0 eq, 1.8 mmol, 0.15 mL) in Et20 mL). The reaction is kept at -780C for 0.5 h and then is allowed to warm to 00C.

After 1.5 h, TLC (10% MeOH in CHCI3) indicates the reaction to be complete. The reaction is quenched with H20 (10 mL) and 1 N HCI (10 mL) and then extracted with Et20 (2 x 10 mL). The aqueous layer is brought to pH 9 with 1 N NaOH and extracted with Et20 (3 x 15 mL), which is dried (MgSO4) and evaporated to a yellow oil (410 mg). This oil is purified by preparative TLC (15% MeOH in CHCI3) to give a yellow oil, which is stirred in EtOH (5 mL) and 1 N HCI (10 mL) for 5 min.

The EtOH is evaporated and the resulting solution extracted with CH2CI2 (3 x mL). The dried organic layers are evaporated to a yellow oil, which is triturated with Et20 to give the title compound as a white powder (110 mg, mp >160 °C (dec).

Example 4 7-tert-Butvl-2.3-dihydro-3,3-dimethvl-5-benzo[blfurancarboxamide Oxime A mixture of 7-tert-butyl-5-cyano-2,3-dihydro-3,3-dimethylbenzo[b]furan (6.39 g, 27.9 mmol), potassium carbonate (15.80 g, 114.0 mmol), hydroxylamine hydrochloride (7.93 g, 114.0 mmol), and 135 mL of ethanol is heated at reflux for h. The reaction mixture is cooled to room temperature, filtered, and concentrated.in vacuo to give a solid residue. Purification by flash column chromatography on silica gel (20% ethyl acetate-hexane methanol-dichloromethane) furnishes 3.13 g of the title compound as a colorless foamy solid: mp 109-110 *C.

WO 97/28148 PCT/US97/01316 11 Example N-Butyl-7-tert-butyl-2,3-dihydro-3, 3 hydrochloride Step 1. 2-Bromo-6-tert-butylthiophenol. To a solution of tetramethylethylenediamine (198.4 mmol, 30 mL) in cyclohexane (140 mL) is slowly added n-BuLi (198.4 mmol, 99.2 mL; 2 M solution in cyclohexane) at 23 The resulting solution is cooled to 0 A solution of 2-tert-butylthiophenol (15.0 g, 90.2 mmol) in cyclohexane (40 mL) is then added at a rate such that the temperature stays below 10°C. The reaction is then stirred at 0 °C for 5 h and is then allowed to warm to 23 °C overnight. To the resulting yellow solution at 23 °C is added sec-BuLi (90.2 mmol, 69.4 mL of 1.3 M solution in cyclohexane) over h. The resulting solution gradually turns orange. After 1.5 h, the orange, cloudy reaction mixture is cannulated into a stirring solution of 1,2dibromotetrafluoroethane (180.4 mmol, 21.5 mL) in THF (50 mL) over 1 h. After addition is complete, the resulting reaction mixture is quenched with 1 N HCI mL), and extracted with hexanes (3 x 100 mL). The hexanes are dried (MgSO4) and evaporated to a dark oil (29.48 This oil is taken up in 1 N NaOH (100 mL), and extracted with CH2CI2 (3 x 50 mL). The organic phase is discarded, and the aqueous phase is acidified with 12 N HCI, and extracted with CH2CI2 (3 x 100 mL).

The organic phase is dried (MgSO4) and evaporated to provide the title compound as a yellow oil.

Step 2. 2-Bromo-6-tert-butylphenyl 2-methallyl thioether. A solution of 2-bromo-6tert-butylthiophenol (12.4 g, 50.6 mmol), K2CO3 (8.44 g, 61.1 mmol), Nal (766 mg, 50.6 mmol), and B-methallylchloride (5.17 mL, 50.6 mmol) in acetone (250 mL) is heated at reflux for 2 h. The reaction is monitored by TLC (hexanes). The reaction mixture is allowed to cool to 23 and the precipitated solids are filtered off. The filtrate is evaporated to a dark yellow oil, which is taken up in hexanes (100 mL) and stirred with silica gel (10 g) for 20 min. The silica gel is filtered off and discarded, and the filtrate is evaporated to yield the title compound as a light yellow oil.

Step 3. 7-tert-Butvl-2,3-dihydro-3,3-dimethylbenzothiophene. A solution of (2bromo-6-tert-butylphenyl)-(2-methallyl)-thioether (9.00 g, 30.0 mmol), di-isopropylethylamine (160 mL, 0.90 mol) and 80% aqueous hypophosphorous acid (58 WO 97/28148 PCTfUS97/01316 12 g, 0.90 mol) in dioxane (450 mL) is deoxygenated by bubbling with N2 for 0.5 h.

The solution is heated to reflux, and a similarly deoxygenated solution of azo-bisiso-butyrylnitrile (1.7 g, 8.8 mmol) in dioxane (5 mL) is added via syringe in 0.5 mL portions in 0.5 h intervals. The reaction is monitored by TLC (hexanes). After 24 h, the reaction mixture is allowed to cool to 23 and partitioned with 1 N HCI (300 mL), brine (100 mL), and Et20 (3 x 150 mL). The combined ethereal extracts are back extracted with 1 N NaOH (3 x 50 mL) and H20 (2 x 50 mL), and then are dried (MgSO4) and evaporated to yield the crude product as a yellow oil. Short path vacuum distillation (85 40 mm Hg) of this material provides the title compound as a faint yellow oil: Step 4: 7-tert-Butyl-5-cyano-2,3-dihydro-3,3-dimethylbenzothioDheneA solution of 7-tert-butyl-2,3-dihydrobenzothiophene (5.0 g, 23 mmol) in CH2CI2 (50 mL) is heated to reflux, and chlorosulfonylisocyanate (3.5 eq, 80 mmol, 7.0 mL) is added in a single portion. The reaction is monitored by TLC EtOAc hexanes). The reaction mixture is then cooled to 0 "C and DMF (10 eq, 0.23 mol, 18 mL) is added.

The solution is allowed to stir at ambient temperature. The solvents are evaporated and the resulting oil partitioned between hexanes (100 mL) and H20 (3 x 50 mL). The aqueous phase is discarded, and the hexanes are dried (MgSO4) and evaporated to a yellow oil which solidifies gradually. This solid is purified by medium pressure chromatography EtOAc hexanes) to give the desired compound.

Step 5 Ethyl 7-tert-butvl-2,3-dihvdro-3,3-dimethvlbenzothienvl-5-carboximidic acid hydrochloride Into a solution of 7-tert-butyl-5-cyano-2,3-dihydro-3,3-dimethylbenzothiophene g, 8.2 mmol) in Et20 (18 mL) and EtOH (3 eq, 24.6 mmol, 1.4 mL) is bubbled HCI gas for 10 min. The resulting red solution is stirred at 23 °C for 4 days. The solvents are evaporated, the red oil triturated with hexanes (15 mL), and the resulting red solid collected by filtration to give the title compound as a red powder of sufficient purity for the next reaction.

WO 97/28148 PCTIUS97/01316 13 Step 6: N-Butyl-7-tert-butvl-2,3-dihydro-3,3-dimethylbenzothienyl-5carboximidamide hydrochloride To a solution of ethyl 7 -tert-butyl-2,3-dihydro-3,3-dimethylbenzothienyl-5carboximidic acid hydrochloride (400 mg) in dioxane (10 mL) is added excess butylamine (0.5 mL). A color change from red to yellow is observed during the addition, and a precipitate forms. The reaction is also monitored by TLC MeOH CHCI3). After 3 h, the white solid is collected by filtration and washed with MeOH to give the title compound as a white powder, mp 240 oC.

Compositions Compositions of the subject invention comprise a safe and effective amount of the subject compounds, and a pharmaceutically-acceptable carrier. As used herein, "safe and effective amount" means an amount of a compound sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of a compound will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular pharmaceuticallyacceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.

Compositions of the subject invention preferably comprise from about 0.1% to about 99.9% by weight of a compound, more preferably from about 20% to about 80%, and most preferably from about 40% to about In addition to the compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term "pharmaceuticallyacceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or lower animal. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or lower animal being treated.

Some examples of substances which can serve as pharmaceuticallyacceptable carriers or components thereof are sugars, such as lactose, glucose WO 97/28148 PCTIUS97/01316 14 and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens®; wetting agents such as sodium lauryl sulfate; coloring agents; flavoring agents, excipients; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

The choice of a pharmaceutically-acceptable carrier to be used in conjunction with a subject compound is basically determined by the way the compound is to be administered.

If the subject compound is to be injected, it is preferably injected nonintravenously; the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with blood compatible suspending agent, the pH of which has been adjusted to about 7.4. Such injectable compositions preferably comprise from about 1% to about 50% of the subject compound, more preferably from about to about 25%, also preferably from about 10 mg to about 600 mg of the subject compound per dose.

Suitable pharmaceutically-acceptable carriers for topical application include those suited for use in lotions, creams, gels and the like. Topical compositions preferably contain from about 1% to about 50% of an emollient, more preferably from about 5% to about 25% of an emollient. Such topical compositions preferably comprise from about 0.1% to about 50%, of the subject compound, more preferably from about 0.5% to about 10%, also preferably from about 5 mg to about 3500 mg per dose.

The preferred mode of administering the subject compound is perorally.

The preferred unit dosage form is therefore tablets, capsules and the like, comprising a safe and effective amount of the compound, which is preferably from about 5 mg to about 3500 mg, more preferably from about 10 mg to about 1000 mg, and most preferably from about 25 mg to about 600 mg. The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Their selection will depend on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be made without difficulty by a person skilled in the art.

WO 97/28148 PCTIS97/01316 Many of the subject compounds are hydrophobic. If it is desired to provide an aqueous-based composition or a composition soluble in or miscible with aqueous media, a solubilizing agent may be included in the composition. Nonlimiting examples of such solubilizing agents include polyethylene glycol, propylene glycol, ethanol, and polyoxyethylene (35) castor oil.

Particularly preferred oral composition carriers suitable for compositions of the subject invention are disclosed in U.S. Patent Nos. 5,189,066 of Kelm Bruns, issued February 23, 1993, entitled "Pharmaceutical Compositions of Tebufelone", and 5,281,420 of Kelm Dobrozsi, issued January 25, 1994, entitled "Solid Dispersion Compositions of Tebufelone", hereby incorporated herein by reference.

Methods Another aspect of the subject invention is methods for treating or preventing diseases characterized by inflammation by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. The term "diseases characterized by inflammation", as used herein, means conditions which are known to involve inflammation, and may include conditions such as arthritis rheumatoid arthritis, osteoarthritis, psoriatic arthritis, juvenile arthritis, Reiter's syndrome, infectious arthritis, and ankylosing spondylitis, systemic lupus, erythematosus and gout), as well as the presence of inflammation whether or not it is associated with an identifiable disease. Diseases characterized by inflammation further may include inflammation in the oral cavity inflammation associated with gingivitis or periodontal disease); inflammation in the gastrointestinal tract, inflammation associated with ulcers and irritable bowel disease); inflammation associated with dermatological diseases psoriasis, acne, and other skin inflammation); inflammation associated with the respiratory tract asthma, bronchitis, and allergies); and inflammation in the central nervous system Alzheimer's disease).

Another aspect of the subject invention is methods for treating or preventing pain by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. Pain which can be treated or prevented by administering the subject compounds may include peripheral pain, menstrual pain, dental pain, and lower back pain.

Another aspect of the subject invention is methods for preventing oxidative damage at inflammatory sites by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. While not limited to a particular mechanism, it is believed that the subject compounds WO 97/28148 PCT/US97/01316 16 inhibit leukotriene synthesis, thereby decreasing neutrophil accumulation at an inflammatory site.

Another aspect of the subject invention is methods for treating or preventing gastric or duodenal ulcers or erosions by administering a safe and effective amount of a subject compound to a human or lower animal in need of such treatment. In particular, such ulcers or erosions caused by ethanol or non-steroidal antiinflammatory drugs (NSAIDs) can be treated and/or prevented by administration of preferred subject compounds.

Appropriate tests for determining the gastrointestinal safety or gastroprotective or gastric healing properties of the subject compounds are known.

Methods for determining acute gastrointestinal safety are disclosed and/or referred to in the following references: Unangst, G.P. Shrum, D.T. Connor, R.D. Dyer, and D.J. Schrier, "Novel 1,2,4-Oxadiazoles and 1,2,4-Thiadiazoles as Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors", J. Med. Chem., Vol. (1992), pp. 3691-3698; and Segawa,Y, O. Ohya, T. Abe, T. Omata, et al., "Antiinflammatory, Analgesic, and Antipyretic Effects and Gastrointestinal Toxicity of the New Anti-inflammatory Drug N-{3-[3-(piperidinylmethyl)phenoxy] propyl}carbamoylmethylthio]ethyl 1 -(p-chlorobenzoyl) 5-Methoxy-2methyl-3indolylacetate", Arzneim.-Forsch./Drug Res., Vol. 42 (1992), pp. 954-992. In the methods disclosed therein, stomachs of the animals are typically examined two hours after dosing a compound. Methods for determining subchronic gastrointestinal safety are disclosed and/or referred to in the following references: Melarange, C. Gentry, et al., "Anti-inflammatory and Gastrointestinal Effects of Nabumetone or Its Active Metabolite, 6-Methoxy-2-naphthylacetic Acid (6MNA)", Dig. Dis. Sci., Vol. 37 (1992), pp. 1847-1852; and Wong, S.J. Lee, et al., "Antiarthritic Profile of BF-389 A Novel Anti-inflammatory Agent With Low Ulcerogenic Liability", Agents Actions, Vol. 37 (1992), pp. 90-91.

Methods for determining acute gastroprotection are disclosed and/or referred to in the following reference: Playford, D.A. Versey, S. Haldane, M.R. Alison, and J. Calan, "Dose-dependent Effects of Fentanyl on Indomethacininduced Gastric Damage", Digestion, Vol. 49 (1991), pp. 198-203. In the method disclosed therein, female Lewis rats (130-175 g) are dosed perorally with the subject compound (40 mg/kg or vehicle at 2 hours and immediately before administration of a gastric damaging dose of indomethacin. The rats are sacrificed 35 4 hours later by CO 2 asphyxiation. Gastric corpus damage (millimeters of hemorrhagic lesions) is measured by digitized imaging.

WO 97/28148 PCTIUS97/01316 17 The preferred mode of administration of the subject compounds is peroral, but other known methods of administration are contemplated as well, e.g., dermatomucosally (for example, dermally, rectally and the like), and parenterally (for example, by subcutaneous injection, intramuscular injection, intraarticular injection, intravenous injection and the like). Ocular administration and inhalation are also included. Thus specific modes of administration include, without limitation, peroral, transdermal, mucosal, sublingual, intranasal, intramuscular, intravenous, intraperitoneal, subcutaneous, and topical administration.

Preferred doses of the subject compounds range from about 0.2 mg/kg to about 70 mg/kg, more preferably from about 0.5 mg/kg to about 12 mg/kg.

Preferred injectable doses comprise from about 0.1 mg/kg to about 10 mg/kg of the subject compound. Preferred topical doses comprise from about 1 mg/cm 2 to about 200 mg/cm 2 of the subject compound applied to the skin surface. Preferred peroral doses comprise from about 0.5 mg/kg to about 50 mg/kg, more preferably from about 1 mg/kg to about 20 mg/kg, more preferably still from about 2 mg/kg to about 10 mg/kg, of the subject compound. Such doses are preferably administered from about once to about six times daily, more preferably from about twice to about four times daily. Such daily doses are preferably administered for at least one week, also preferably for at least two weeks, also preferably at least one month, also preferably for at least 2 months, also preferably for at least 6 months, 1 year, 2 years, or more.

Compositions and Method Examples The following non-limiting examples illustrate the subject invention.

Example A Pharmaceutical compositions in the form of tablets are prepared by conventional methods, such as mixing and direct compaction, formulated as follows: Ingredient Quantity (mq per tablet) Compound 1 200 Microcrystalline Cellulose 100 Sodium Starch Glycollate Magnesium Stearate 3 When administered orally two times daily, the above composition significantly reduces the inflammation in a patient suffering from rheumatoid arthritis. A significant benefit is also achieved by twice daily administration of this composition to a patient suffering from osteoarthritis.

Example B WO 97/28148 PCT[JS97/01316 18 A pharmaceutical composition in capsule form is prepared by conventional methods, formulated as follows: Ingredient Quantity (mq per capsule) Compound 2 200 Lactose To fill to volume of capsule The above capsule administered orally once a day substantially reduces the symptomology of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example C A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows: Ingredient Quantity Compound 3 200 mg.

EtOH 4 ml Methyl cellulose 0.4 mg Distilled water 76 ml Tween 80 1.6 ml ml of the above composition administered perorally once a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis.

Example D A pharmaceutical composition in liquid form is prepared by conventional methods, formulated as follows: Ingredient Quantity Microcrystalline (micronoized) 200 mg Compound 4 Avicel (microcrystalline cellulose) 50 mg Tween 80 1.6 ml Methyl cellulose 0.4 mg Deionized water 80 ml 50 ml of the above composition administered perorally twice a day substantially reduces the symptoms of a patient afflicted with rheumatoid arthritis or osteoarthritis.

While particular embodiments of the subject invention have been described, it would be obvious to those skilled in the art that various changes and modifications to the compositions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

18a The term "comprises", and grammatical variations thereof such as "comprising" when used in the description and claims does not preclude the presence of additional features, integers, steps or components; or groups thereof.

Claims

1. A compound having the structure: NW Y Y (CH2)n I R2 Z wherein n is from. 1 to 3; X is selected from the group consisting of O, S, SO, or SO 2 Y is independently hydrogen or straight, branched or cyclic alkyl having from 1 to 4 carbon atoms, or the Y's are bonded together to form an alkanyl ring having from 3 to 7 atoms; Z is hydrogen or unsubstituted straight, branched or cyclic alkyl having from 3 to 10 atoms other than hydrogen; W is hydrogen or straight, branched or cyclic alkyl, aryl, hydroxy or alkoxy; and R, and R 2 are independently hydrogen, straight, branched or cyclic alkyl having from one to 10 carbon atoms, aryl, alkyl, heterocyclyl, heteroaryl, hydroxy, or alkoxy; or R, and R, are bonded together to form a ring having from 3 to 7 atoms wherein one to three atoms may be heteroatoms.

2. The compound of Claim 1 wherein X is oxygen or sulphur; and W is hydrogen or hyroxyl.

3. The compound of Claim 1 wherein each Y is independently selected from the group consisting of hydrogen, methyl and ethyl; and Z is selected from the group consisting of C 4 -C 6 branched alkanyl having 2 branches, C 3 -C 6 cycloalkanyl.

4. The compound of Claim 3 wherein R, is hydrogen or methyl, and R 2 is nydrogen, C,-C6 straight or single-branched alkyl or straight alkyl with a terminal cyclic alkyl, saturated or unsaturated with one double bond between non-terminal carbon atoms, or C3-C6 cycloalkanyl or R, and R 2 are bonded together to form a ring having from 3 to 7 atoms. The compound of Claim 4 wherein X is oxygen, R, and R 2 are hydrogen, methyl or butyl.

6. The compound of Claim 5 wherein both Y are methyl, and Z is t-butyl.

7. The compound of Claim 6 wherein W is OH or hydrogen and n is one.

8. The compound of Claim 3 wherein R, and R 2 are bonded to form a ring selected from the group selected from the group consisting of -(CH 2 4 -(CH 2 5 or -(CH 2 6

9. The compound of Claim 8 wherein both Y are methyl, and Z is t-butyl. The compound of Claim 9 wherein X is oxygen, and R, and R 2 are

11. The compound of Claim 10 wherein W is hydrogen and n is one.

12. A composition comprising a compound of Claim 1 and a pharmaceutically-acceptable carrier.

13. A method of treating inflammation or pain comprising administration, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound of Claim 1.

14. A method of treating arthritis comprising daily peroral administration, to a human in need of such treatment, of from about 1 mg/kg to about 20 mg/kg of a compound of Claim 1. A composition comprising a compound of Claim 7 and a pharmaceutically-acceptable carrier.

16. A method of treating inflammation or pain comprising administration, to a human or lower in need of such treatment, of a safe and effective amount of a compound of Claim 7.

17. A method of treating arthritis comprising daily peroral administration, to a human in need of such treatment, of from about 1 mg/kg to about 20 mg/kg of a compound of Claim 7.

18. A composition comprising a compound of Claim 11 and a pharmaceutically-acceptable carrier.

19. A method of treating inflammation or pain comprising administration, to a human or lower animal in need of such treatment, of a safe and effective amount of a compound of Claim 11. A method of treating arthritis comprising daily peroral administration, to a human in need of such treatment, of from about 1 mg/kg to about 20 mg/kg of a compound of Claim 11.

21. A compound as claimed in Claim 1 substantially as hereinbefore described with reference to the Examples.

22. A composition as substantially described hereinbefore with reference to the Examples.

23. A method of treating inflammation, pain or arthritis substantially as hereinbefore described with reference to the Examples. DATED this 3 rd day of January 2001 VANDERBILT UNIVERSITY WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P2643AU00 LCG/RBP/RES